Development of drugs targeting hepatitis B x-protein

• Project/Area Number: 24659359
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: SAKAMOTO NAOYA 北海道大学, 医学(系)研究科(研究院), 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): NAKANISHI Mitsuru 北海道大学, 医学研究科, 特任助教 (10392250)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ウイルス / 医学 / ウイルス学 / 基礎研究 / B型肝炎

Research Abstract

We have conducted study project to develop new classes of antiviral drug against hepatitis B virus (HBV). In the study period, we obtained the following results. (1) HBV expression plasmid which selectively lacks HBX protein showed decreased expression levels as compared with wild type when transfected into humans hepatoma Huh7 cells. (2) Mutant HBV expression plasmids were constructed in which 4 consecutive alanine substitution were introduced in the HBX protein coding frame. By using the mutant HBX plasmids, we found AP1 transactivator domain in C-terminal of HBX.

Research Products

• [Journal Article] The J6JFH1 strain of hepatitis C virus infects human B cells with low replication efficacy (2014)
  • Author(s): Masato Nakai, Tsukasa Seya, Misako Matsumoto, Kunitada Shimotohno, Naoya Sakamoto, and Hussein H Aly
  • Journal Title: Viral Immunology Volume: (in press)
  • NAID: 120005468145
  • Peer Reviewed
• [Journal Article] Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor κB/mitogen-activated protein kinase. (2014)
  • Author(s): Chuma M, Sakamoto N, Nakai A, Hige S, Nakanishi M, Natsuizaka M, Suda G, Sho T, Hatakaka K, Matsuno Y, Yokoo H, Kamiyama T, Taketomi A, Fujii G, Tashiro K, Hikiba Y, Fujimoto M, Asaka M, Maeda S
  • Journal Title: Carcinogenesis Volume: Epub ahead of print Issue: 2 Pages: 272-281
  • DOI: 10.1093/carcin/bgt343
  • Peer Reviewed
• [Journal Article] Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C. (2014)
  • Author(s): Maekawa S, Enomoto N
  • Journal Title: J Gastroenterol. Volume: 49(1) Issue: 12 Pages: 163-164
  • DOI: 10.1371/journal.pone.0082299
  • Peer Reviewed
• [Journal Article] The J6JFH1 strain of hepatitis C virus infects human B cells with low replication efficacy. (2014)
  • Author(s): Masato Nakai, Tsukasa Seya, Misako Matsumoto, Kunitada Shimotohno, Naoya Sakamoto, and Hussein H Aly
  • Journal Title: Viral Immunology Volume: in press
  • NAID: 120005468145
  • Peer Reviewed
• [Journal Article] Hypoxia-inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors (2013)
  • Author(s): Ohnishi S, Maehara O, Nakagawa K, Kameya A, Otaki K, Fujita H, Higashi R, Takagi K, Asaka M, Sakamoto N, Kobayashi M, Takeda H
  • Journal Title: Plos One Volume: 8 Issue: 6 Pages: e66255-e66255
  • DOI: 10.1371/journal.pone.0066255
  • NAID: 120005326763
  • Peer Reviewed
• [Journal Article] Wnt5a Signaling Mediates Biliary Differentiation of Fetal Hepatic Stem/Progenitor Cells (2013)
  • Author(s): Kakinuma S, Kiyohashi K, Kamiya A, Sakamoto N, Nitta S, Yamanaka H, YoshinoK, Fujiki J, Murakawa M, Kusano-Kitazume A, Shimizu H, Okamoto R, Azuma S, Nakagawa M, Asahina Y, Tanimizu N, Kikuchi A, Nakauchi H, and *WatanabeM
  • Journal Title: Hepatology Volume: (in press) Issue: 6 Pages: 2502-2513
  • DOI: 10.1002/hep.26293
  • Peer Reviewed
• [Journal Article] NX-PVKA assay, a conventional but refined prognostic biomarker for Hepatocellular carcinoma. (2013)
  • Author(s): Sakamoto N
  • Journal Title: Journal of Gastroenterol and Hepatol Volume: 28 Issue: 5 Pages: 755-756
  • DOI: 10.1111/jgh.12138
  • Peer Reviewed
• [Journal Article] Hepatitis C virus replication is modulated by the interaction of non-structural protein NS5B and fatty acid synthase. (2013)
  • Author(s): Huang JT, Tseng CP, Liao MH, Lu SC, Sakamoto N, et al.
  • Journal Title: Journal of Virology Volume: (Epub) Issue: 9 Pages: 4994-5004
  • DOI: 10.1128/jvi.02526-12
  • Peer Reviewed
• [Journal Article] A multi-center survey of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic Hepatitis C in Japan (2013)
  • Author(s): Oze T, Hiramatsu N, Mita E, Akuta N, Sakamoto N, et al.
  • Journal Title: Hepatol Res Volume: 43 Issue: 1 Pages: 35-43
  • DOI: 10.1111/j.1872-034x.2012.01056.x
  • Peer Reviewed
• [Journal Article] Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C. (2013)
  • Author(s): Kurosaki M, Sakamoto N, Asahina Y, Izumi N et al
  • Journal Title: J Med Virol Volume: 85 Issue: 3 Pages: 449-458
  • DOI: 10.1002/jmv.23497
  • Peer Reviewed
• [Journal Article] Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C. (2013)
  • Author(s): Kohjima M, Enjoji M, Sakamoto N, et al.
  • Journal Title: J Med Virol Volume: 85 Issue: 2 Pages: 250-260
  • DOI: 10.1002/jmv.23464
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [Journal Article] 肝炎ウイルス学近年の進歩 (2013)
  • Author(s): 坂本直哉
  • Journal Title: 診断と治療 Volume: 101(9) Pages: 1283-1286
• [Journal Article] Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients (2012)
  • Author(s): Saito H, Ito K, Sugiyama M, Matsui T, Aoki Y, Imamura M, Murata K, Masaki N, Nomura H, Adachi H, Hige S, Enomoto N, Sakamoto N, Kurosaki M, Mizokami M, Watanabe S
  • Journal Title: Hepatol Res Volume: 42(10) Issue: 10 Pages: 958-65
  • DOI: 10.1111/j.1872-034x.2012.01013.x
  • Peer Reviewed
• [Journal Article] Inhibition of Hepatitis C Virus Replication and Viral Helicase by Ethyl Acetate Extract of the Marine Feather Star Alloeocomatella polycladia (2012)
  • Author(s): Yamashita A, Maekawa S, et al
  • Journal Title: Mar.Drugs Volume: 10 Issue: 4 Pages: 744-761
  • DOI: 10.3390/md10040744
  • Peer Reviewed
• [Journal Article] Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C. (2012)
  • Author(s): Kobayashi T, Hige s, Sakamoto N, et al.
  • Journal Title: J Gastroenterol Volume: 47 Issue: 11 Pages: 1228-1237
  • DOI: 10.1007/s00535-012-0579-y
  • NAID: 10031126955
  • Peer Reviewed
• [Journal Article] Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Amphimedon sp. (2012)
  • Author(s): Fujimoto Y
  • Journal Title: PLoS One. Volume: 7 Issue: 11 Pages: 744-761
  • DOI: 10.1371/journal.pone.0048685
  • Peer Reviewed
• [Journal Article] Cyclophilin A and nuclear factor of activated T cells are essential in cyclosporin A-mediated suppression of polyomavirus BK replication (2012)
  • Author(s): Li YJ, Wu HH, Weng CH, Chen YC, Hung CC, Yang CW, Wang YL, Sakamoto N, Tian YC.
  • Journal Title: Am J Transplantation Volume: 12(9) Issue: 9 Pages: 2348-2362
  • DOI: 10.1111/j.1600-6143.2012.04116.x
  • Peer Reviewed
• [Journal Article] Ochanomizu Liver Conference Study Group : Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C (2012)
  • Author(s): Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K, Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M, Watanabe M.
  • Journal Title: Hepatol Int Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Suppression of hepatitis C virus replicon by adenovirus vector-mediated expression of tough decoy RNA against miR-122a. Virus Research (2012)
  • Author(s): Sakurai F, Furukawa N, Higuchi M, Okamoto S, Ono K, Yoshida T, Kondoh M, Yagi K, Sakamoto N, Katayama K, Mizuguchi H
  • Journal Title: EPub ahead of Print Volume: 165 Issue: 2 Pages: 214-218
  • DOI: 10.1016/j.virusres.2012.02.003
  • Peer Reviewed
• [Journal Article] Let-7b is a novel regulator of hepatitis C virus replication. Cell Mol Life Sci 2012 (2012)
  • Author(s): Cheng J-C, Yeh YJ, Tseng CP, Hsu SD, Chang YL, Sakamoto N, Huang HD
  • Journal Title: EPub ahead of Print Volume: 69 Issue: 15 Pages: 2621-2633
  • DOI: 10.1007/s00018-012-0940-6
  • Peer Reviewed
• [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C (2012)
  • Author(s): Kurosaki M, Sakamoto N, Nakagawa M, et al.
  • Journal Title: J Hepatol Volume: 56(3) Issue: 3 Pages: 602-608
  • DOI: 10.1016/j.jhep.2011.09.011
  • Peer Reviewed
• [Journal Article] Inhibition of hepatitis C virus NS5B polymerase by S-trityl-L-cysteine derivatives (2012)
  • Author(s): Kaushik-Basu N, Sakamoto N
  • Journal Title: Eur J Med Chem Volume: 49 Pages: 191-199
  • DOI: 10.1016/j.ejmech.2012.01.010
  • Peer Reviewed
• [Journal Article] Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication (2012)
  • Author(s): Kusano-Kitazume A, Sakamoto N, Okuno Y, Sekine-Osajima Y, Nakagawa M, Kakinuma S, Kiyonashi K, Nitta S, Murakawa M, Azuma S, Nishimura-Sakurai Y, Hagiwara M, Watanabe M
  • Journal Title: Antimicrob Agent Chemother Volume: 56(3) Issue: 3 Pages: 1315-23
  • DOI: 10.1128/aac.05764-11
  • Peer Reviewed / Open Access
• [Journal Article] Age and total ribavirin dose are independent predictors of relapse after interferon therapy in chronic hepatitis C revealed by data mining analysis (2012)
  • Author(s): Masayuki Kurosaki
  • Journal Title: Antiviral Therapy Volume: 17(1) Issue: 1 Pages: 35-43
  • DOI: 10.3851/imp1923
  • Peer Reviewed
• [Journal Article] C型肝炎の近未来治療 (2012)
  • Author(s): 坂本直哉
  • Journal Title: 化学療法の領域 Volume: 28(S-1) Pages: 1134-1140
• [Journal Article] 座談会-B型肝炎 : 克服へのロードマップ (2012)
  • Author(s): 坂本直哉
  • Journal Title: 肝胆膵 Volume: 65(4) Pages: 763-778
• [Journal Article] C型肝炎治療薬テラプレビル (2012)
  • Author(s): 坂本直哉
  • Journal Title: 薬局 Volume: 63 (1) Pages: 123-128
• [Journal Article] HBV無症候性キャリアの自然経過と診療 (2012)
  • Author(s): 中西満、坂本直哉
  • Journal Title: 肝胆膵 Volume: 65 (4) Pages: 627-634
• [Journal Article] C型肝炎治療のEBM : テラプレビル (2012)
  • Author(s): 坂本直哉
  • Journal Title: 肝胆膵 Volume: 64(3) Pages: 319-325
• [Journal Article] HBV無症候性キャリアの自然経過と診療 (2012)
  • Author(s): 中西満、坂本直哉
  • Journal Title: 医学のあゆみ Volume: 242 (5) Pages: 401-406
• [Journal Article] Association of gene expression involving innate immunity and genetic variation in IL28B with antiviral response (2011)
  • Author(s): Asahina Y, Sakamoto N, et al
  • Journal Title: Hepatology Volume: 55(1) Issue: 1 Pages: 20-29
  • DOI: 10.1002/hep.24623
  • Peer Reviewed
• [Journal Article] Suppression of Hath1 gene expression directly regulated by Heslvia Notch signaling is associated with goblet cell depletion in ulcerative colitis (2011)
  • Author(s): Zheng X, Nakamura T, et al
  • Journal Title: Inflamm Bowel Dis Volume: 17 Issue: 11 Pages: 2251-2260
  • DOI: 10.1002/ibd.21611
  • Peer Reviewed
• [Journal Article] Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy (2011)
  • Author(s): Kadokura M, Nakagawa M, Sakamoto N, Watanabe M, et al.
  • Journal Title: Hepatol Int Volume: 5(3) Issue: 3 Pages: 789-799
  • DOI: 10.1007/s12072-011-9267-x
  • Peer Reviewed
• [Journal Article] Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection (2011)
  • Author(s): Yoshida T, Sakamoto N, et al
  • Journal Title: Biochem Biophys Res Commun Volume: 416(1-2) Issue: 1-2 Pages: 119-124
  • DOI: 10.1016/j.bbrc.2011.11.007
  • Peer Reviewed
• [Journal Article] A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors (2011)
  • Author(s): Takaya D, Sakamoto N, et al.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 19(22) Issue: 22 Pages: 6892-6905
  • DOI: 10.1016/j.bmc.2011.09.023
  • Peer Reviewed
• [Journal Article] NCV-NS4B蛋白とIFN発現計シグナル分子との分子間相互作用の解析 (2011)
  • Author(s): 新田沙由梨,坂本直哉
  • Journal Title: 消化器と免疫 Volume: 48 Pages: 174-177
• [Presentation] Let-7b is a novel regulator of hepatitis C virus replication. J Hepatol 2011; in submission.. 19th. International Meeting on Hepatitis C Virus &Related Viruses. (2012)
  • Author(s): Yeh YJ, Tseng CP, Sakamoto N,et al.
  • Organizer: 19th. International Meeting on Hepatitis C Virus & Related Viruses.
  • Place of Presentation: Palazzo del Cinema（イタリア、ベニス）
• [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎治療の効果・安全性の最適化（シンポジウム6ゲノムワイド検索（GWAS）と消化器疾患） (2012)
  • Author(s): 中川美奈、坂本直哉、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] IL-6を介したC型慢性肝炎のインターフェロン治療抵抗性機構（シンポジウム3 ） (2012)
  • Author(s): 坂本直哉、中川美奈、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京）